PROJECT SUMMARY/ABSTRACT African American (AA) smokers bear a disproportionate share of tobacco-related morbidity and mortality. Quitting smoking is the single most important change a smoker can make to improve their health, yet AA experience greater difficulty quitting relative to other racial/ethnic groups despite being lighter smokers (< 10 cigarettes per day; CPD) and making more attempts. In the majority of smoking cessation trials, participants stay on the pharmacotherapy to which they were randomized through the end of the study. These trials do not provide any opportunity to make changes to pharmacotherapy during the course of treatment despite evidence that the smokers who fail to achieve abstinence within 4 weeks of initiating treatment never achieve long-term abstinence. Optimized approaches that change or augment pharmacotherapy have been successfully used in other disciplines but are relatively new to tobacco dependence research. Given that tobacco dependence is a chronic, relapsing disorder characterized by multiple failed quit attempts, the high degree of heterogeneity in treatment response, and the absence of new pharmacotherapy advances, the best opportunities to improve tobacco treatment for AA smokers lie in the use of novel methodologies that explore how to optimize treatment by providing intensive smoking cessation counseling while altering the timing, sequencing, or combining of pharmacotherapies to maximize efficacy. The objectives of this application are to 1) evaluate short- and long- term efficacy of optimized (OPT) versus enhanced usual care (UC) treatment on biochemically-verified 7-day abstinence in African American smokers, 2) identify mediators and moderators of treatments effect on abstinence, 3) characterize the proportion of subjects requiring optimization and the rate of verified abstinence along each optimization pathway, and 4) characterize treatment process factors (e.g., withdrawal, craving) over time in response to optimized treatment. These objectives will be accomplished through a randomized open- label optimized treatment trial for smoking cessation in 392 African American smokers. Participants randomized to OPT (n=196) will receive smoking cessation counseling, nicotine patch, and up to two pharmacotherapy adaptations to bupropion and/or varenicline based on verified smoking status at Weeks 2 and 6. Participants randomized to enhanced UC (n=196) will receive the same smoking cessation counseling and nicotine patch; no adaptations in pharmacotherapy will be made. At the conclusion of the trial we will provide the research and clinical communities with knowledge about the efficacy of optimized versus non- optimized approaches for achieving short- and long-term abstinence for AA , as well as an understanding of the mediators and moderators of treatment effect. The innovative study design evaluates a major shift in the approach to tobacco dependence treatment and, if effective, could have broad treatment implications for the nearly 6 million AA adult smokers in the U.S.